Introduction:

Endothelin-1 (ET-1) causes long-lasting vasoconstrictor and vasopressor responses mediated by quasi-irreversible binding to ET_A-receptors. Upregulation of ET-1 is in at least salt-sensitive hypertension counterbalanced by the sensory-motor neurotransmitter calcitonin gene-related peptide (CGRP). We tested whether this CGRP promotes dissociation of ET-1/ ET_A-receptor complexes.

Methods:

Reactivity of isolated arteries was monitored using wire-myography. ET_A-receptor binding was studied with rhodamine-labelled ET-1 (Rh-ET-1) and 2-photon laser scanning microscopy of intact vital arteries in the presence of BQ788 (1 M). Blood pressure and local blood flow were measured in anesthetized rats.

Results:

In mouse and rat mesenteric arteries (MRA), ET-1 (16 nM) caused "persistent" contractions that could be terminated by capsaicin (1 M) and CGRP (0.1 M) but that were only transiently reduced by ACh (10 M) or BQ123 (1 M). Also, in rat epigastric, renal, saphenous, spermatic and splenic arteries, ET-1 (32 nM) caused "persistent" contractions that were not reversed by BQ123 but that could be terminated by CGRP. In rat MRA, binding of Rh-ET-1 was prevented by BQ123 but could not be reversed by this ET_A-antagonist. Yet, capsaicin or CGRP reversed pre-existing binding of Rh-ET-1. In vivo, the long-lasting pressor responses to ET-1 (1 g/kg i.v.) and to big-ET-1 (1 g/kg i.v.) were only transiently reduced by Na-nitroprusside (30 g/kg i.v.) but were terminated by CGRP (3 g/kg i.v.). The latter was at least partly due to reduction of the increased resistance in the skeletal muscle and renal vascular beds.

Conclusion:

Arterial vasoconstrictor responses to ET-1 are resistant to ET_A-antagonism and endothelium-derived relaxing factors such as NO but are selectively abolished by CGRP-receptor stimulation that promotes dissociation of ET-1/ ET_A-receptor complexes.